Migraine is a painful syndrome characterized by unilateral, pulsating headaches, nausea, vomiting, and sensitivity to light and sounds. It is generally accepted that 23 million Americans suffer from migraine and that the incidence has been increasing over the last decade.
There are a number of recognized migraine therapeutic drugs. One recognized treatment for migraine is the administration of ergotamine or ergotamine-like agents. Another treatment is the administration of newer therapeutic agents known as serotonin agonists or 5HT agonists. Yet another treatment involves the administration of caffeine with ergots or other pharmacologic agents. While no more than sporadically effective, all of these conventional art recognized migraine drugs are thought to initially relieve migraine predominantly by causing vasoconstriction. Unfortunately, these conventional art recognized migraine drugs are associated with significant negative side effects that are linked to excessive vasoactivity in regions of the body not involved in the pathogenesis of migraine. This remote vasoactivity is an effect without any therapeutic benefit to the treatment of migraine. These vasoactive drugs are, in fact, contraindicated in patients with coexisting cardiovascular diseases, or the risk of cardiovascular diseases, such as hypertension, coronary artery disease, or peripheral vascular diseases. Other reported significant side effects are chest pain or pressure, flushing, generalized tingling sensations, nausea, vomiting, pain in the legs and arms, asthenia, drowsiness, and dizziness. In addition, agents such as ergots and caffeine are potentially addictive with well document withdrawal symptoms. Acute ergotism is a particularly pernicious side effect of ergot drugs, and is characterized by severe central and peripheral vasoconstriction, sometimes resulting in amputation of the affected limbs and/or digits, nausea, vomiting, diarrhea, colic, headache, vertigo, paresthesia, and possibly convulsive seizures. Chronic ergotism is characterized by intermittent claudication, muscle pains, numbness, and cold extremities as well as other gastrointestinal and CNS side effects.
The recognized migraine drugs act most quickly when they are administered by the parenteral route. Of course, no matter how administered, therapeutic relief of migraine is often not obtained. When given orally, the recognized migraine drugs act significantly more slowly than when parenterally administered such that pain relief, when obtained, may not be apparent for up to 2-3 hours post-administration. Considering the contraindications, risk of side effects, and slow onset of action of the ergot preparations and the new serotonin agonists when given orally, an improved migraine drug formulation for oral administration is needed for millions of migraine sufferers.
In some forms of migraine, certain patients have found total or partial relief with the use of non-prescription analgesics such as acetaminophen, aspirin, ibuprofen, and other non-steroidal anti-inflammatory agents, including naproxen and naproxen sodium. However, these agents, when taken alone, are rarely effective in providing complete and rapid relief of all the symptoms of migraine, especially when the symptoms of the attack already include nausea or vomiting. Moreover, there onset of action is slow such that relief sometimes does not occur for at least several hours.
As outlined by K. M. A. Welch (New Engl J Med, 1993:329; 1476-1483), the initial dosages of the analgesics useful for the treatment of migraine are: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and, ibuprofen 200 mg. After oral dosing, peak plasma concentrations in subjects not experiencing a migraine attack usually occur at or about 1 hour for aspirin and acetaminophen, and between 1-2 hours for naproxen sodium, tolfenamic acid, and ibuprofen.
It is of particular importance to note, however, that absorption of these and other agents during a migraine attack has been shown to be impaired in comparison with absorption rates when no migraine attack is occurring. Without being bound by any particular theory, it is believed that the observed slower absorption, and delayed plasma peak and onset of therapeutic action, is due to gastric stasis during migraine attacks.
Migraine attacks are debilitating to migraine sufferers. A migraine drug formulation that is
(i) is side-effect reduced or side effect free both in being PA1 (ii) a statistically significant increase in the percentage of subjects who respond within 1 hour of administration, and, in some groups, PA1 (iii) less than about 30% relapse within the 4 to 24 hour post-administration period (and preferably less than about 20%) represents a significant and surprising advance in migraine therapy.
(i)(a) ergotism-free, and, PA2 (i)(b) absent supra-vasoactive response, and which exhibits a relief profile that represents
Thus, non-vasoactive side-effect reduced or side effect free therapy requires exclusion of vasoactive agents like the ergots, serotonin agonists such as sumatriptan (including related 5HT agonist heterocyclic compounds as described in U.S. Pat. No. 4,816,470 to Dowle et al., the teachings of which are incorporated by reference) and caffeine. Of particular note is a migraine drug formulation that is delivered in a "sequential dissolve manner" reduces, prevents, or eliminates gastric stasis and the nausea/vomiting noted to occur with a migraine attack and allows for a faster rate of absorption of the presently recognized migraine drugs. This "side-effect reduced/absorption enhanced" formulation will, in turn, provide enhanced therapeutic effect compared to single administration of the analgesic alone. As more fully defined below, "enhanced" indicates that relief will be faster, or observed in a greater number of migraine headaches, or in a greater number of migraine sufferers, and with a significantly reduced incidence and/or severity of side-effects, or a broader group of symptoms will be relieved. Enhanced also includes the abortion of incipient migraine attacks.
One nausea relieving gastric absorption and gastric motility enhancing agent is metoclopramide. Metoclopramide has been described as having a minimal level of 5HT-3 antagonist properties. Such properties are not believed to rise to the level of a therapeutic analgesic. It is noted that parenteral administration of metoclopramide has been associated with relief of migraine symptoms. However, oral administration of metoclopramide has not been found to provide migraine relief. Thus, as a sole therapeutic agent for migraine relief, orally administered metoclopramide has not been known to be therapeutically effective. Metoclopramide does have potent anti-nausea and anti-vomiting properties. As nausea and vomiting are associated with is migraine attacks, metoclopramide given parenterally can provide symptomatic relief of these symptoms of migraine. Oral administration of metoclopramide formulations currently available are absorbed too slowly to provide adequate and timely relief of migraine associated nausea and vomiting. One formulation described in U.S. Pat. No. 4,380,540 to Poyser et al. discloses aspirin intermixed with metoclopramide, without reference to NSAID. U.S. Pat. No. 4,380,540 does not teach or suggest separating the acid aspirin component from the basic metoclopramide component. In fact, U.S. Pat. No. 4,380,540 particularly notes the uniform dispersion of metoclopramide throughout the aspirin. It is noted that metoclopramide is a proton acceptor (basic) as the active moiety, and even acid salts of metoclopramide are proton acceptors (Lewis base) in the dissolved state. When in chemical contact in tablets, metoclopramide and an acid analgesic such as aspirin or NSAID will experience unacceptable degradation (over 5%) in a matter of two to three weeks at ambient (about 150 to about 20.degree. C.) and further about 25% degradation or deactivation in three weeks.
Given by the intravenous route, peak plasma levels of metoclopramide occur in 5 minutes. Given by the oral route, conventional tablets of metoclopramide provide peak plasma levels much more slowly with peak plasma levels occurring between one and two hours in subjects experiencing a migraine attack. The therapeutic literature suggests that the minimum oral dose for relief of nausea is 10 mg during a migraine episode. From onset, the antinausea action of metoclopramide appears to be at least 45-90 minutes using conventional tablets given orally. However, it has now been discovered that local improvement in gastric motility can be observed in some subjects with oral doses as low as about 1 mg, but more commonly from about 4 mg to about 20 mg, with particular emphasis from about 5 to less than about 10 mg, and further dependent on broad distribution over the surface of the gastric mucosa (usually in the solubilized form). As noted below, a dosage of metoclopramide that performs this function is termed an effective local gastric concentration. Without being bound by any particular theory, it is believed that in a migraineur having a migraine attack, metoclopramide locally available (i e., in the stomach and at the pyloric sphincter) facilitates relaxation of the pylorus otherwise in stasis, which immediately introduces the NSAID into the small bowl, the site of absorption for the NSAID. Such pyloric relaxation is a possible result of desensitization of the gastrointestinal tract to systemic neurotransmitters.
Headache recurrence after successful initial treatment is another weakness of some currently available anti-migraine preparations. That is, after a dosage of a therapeutic agent has been administered to a subject in an amount to initially effectively treat a migraine attack, and migraine palliation has been observed, migraine symptoms occur again from as soon as about 1-8 hours after first relief to about 12 to 24 hours later. It will be appreciated that individual migraineurs display individualized symptoms and timing for this phenomenon as will treatment with particular therapeutic agents.
The headache which occurs under the circumstances described above has been variously and interchangeably termed a "rebound," "relapse," "recurrent," "follow on," or "secondary" headache. The terms not withstanding, it is presently unknown as to whether this later headache is a continuation of the physiological chain of events that caused original headache, or a new headache due to other or repeated, but unrelated, underlying pathology. It is also possible that the follow on headache is a response to therapeutic agents which initially were successful in treating the initial migraine symptoms. The terms "rebound," "relapse," "recurrent" "follow on," and "secondary" (as defined below) are considered synonymous as used herein without inferring a mechanism or cause of migraine headache.
It has been reported that of the 50 to 70% of patients who experience migraine symptom relief within 2 hours from initial dosing with a 5HT agonist, 30-50% experience migraine symptoms again within the next 1-24 hours. In view of the extreme discomfort and long duration of pain that characterizes migraine headaches, a therapy that reduces or avoids rebound migraine is of substantial importance.
In the practice of this invention, of the analgesic agents mentioned above, the NSAID, naproxen sodium, is particularly useful agent to prevent the relapse headache. While it has not previously been found particularly useful, in the formulation and method of this invention, it has been discovered that its 13 hour half-life and long duration of action is useful when coupled with metoclopramide in specific formulations. Furthermore, naproxen sodium is non-vasoactive in the sense of direct vasoactivity. This is established by standard pharmacologic methods utilized to determine vasoactivity, with particular reference to The Pharmacological Basis of Therapeutics, Ed. L. S. Goodman and A. Gilman, eighth edition (Pergamon Press, New York 1990) the teachings of which are incorporated by reference.
A novel oral unit dosage form containing the active ingredients of metoclopramide and naproxen sodium, and absent caffeine, ergot drugs or other 5HT agonists is a formulation that will provide improved therapeutic non-vasoactive migraine relief with reduced side effects and reduced incidence of relapse. Naproxen tablets and metoclopramide tablets (and other dosage forms of these drugs) are commercially available. The available dosage forms are inadequate to provide for rapid sequential dissolution, rapid absorption and, ultimately, rapid, complete and long-lasting migraine symptom relief.
The intended therapeutic result, i.e., rapid, complete, and long-lasting migraine symptom relief, is produced with a unit dosage form that allows the metoclopramide component to dissolve first and extremely quickly, followed within a few minutes by the rapid dissolution and absorption of the naproxen sodium component. Particular excipients, compaction pressures and particles affect such mobilization, and particular note is made of naproxen sodium crystals in the 10 .mu.m to 200 .mu.m range (more particularly about 90 .mu.m to about 150 .mu.m) which particle sizes assist in permitting rapid absorption. Such a dosage form speeds the absorption of both active ingredients producing an enhanced therapeutic effect in the treatment of migraine.
Note is made of certain publications presenting aspects of the therapeutic treatment of migraine, the teachings of which are incorporated by reference: 1. "Treatment of the migraine attack." Silberstein S. D.; Current Opinion in Neurology 1994;7:258-263; 2. "Drug therapy of migraine." Welch, K. M. A.; New Engl J Med; 1993;329: 1476-1483; 3. "Recent advances in the acute management of migraine and cluster headaches." Kumar K. L.; J Gen Int Med 1994;9:339-348; 4. "Abortive Migraine Therapy with Oral Naproxen Sodium Plus Metoclopramide Plus Ergotamine Tartrate With Caffeine" Saadah, H., Headache, 32:95-97 (1992); and "Pharmacokinetic aspects of combination of metoclopramide and paracetamol. Results of human kinetic study and consequences for migraine patients." Becker, Arzneimittelforshung, 42(4), 552-555 (1992).